Alleviation of doxorubicin-induced cardiomyocyte death through miR-147-y-mediated mitophagy

被引:8
作者
Gao, Hongbin [1 ,2 ]
Xian, Gaopeng [3 ,4 ]
Zhong, Guoheng [3 ,4 ]
Huang, Bihong [2 ]
Liang, Shi [2 ]
Zeng, Qingchun [3 ,4 ]
Liu, Yungang [1 ]
机构
[1] Southern Med Univ, Guangdong Prov Key Lab Trop Dis Res, Sch Publ Hlth, Dept Toxicol, Guangzhou 510515, Peoples R China
[2] Guangdong Lab Anim Monitoring Inst, Guangdong Prov Key Lab Lab Anim, Guangzhou 510663, Peoples R China
[3] Guangzhou Regenerat Med & Hlth Guangdong Lab, Bioland Lab, Guangzhou 510005, Peoples R China
[4] Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Shock & Microcirculat, Dept Cardiol, Guangzhou 510515, Peoples R China
关键词
Cardiomyocyte; Doxorubicin; miR-147-y; Mitophagy; Apoptosis; MITOCHONDRIA; PARKIN;
D O I
10.1016/j.bbrc.2022.04.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Doxorubicin (DOX) is a commonly used antitumor drug. However, it may cause severe cardiotoxicity, apoptosis being a major change. A recent report indicates that miR-147 expression is decreased in the myocardium of a myocardial infarction model, suggesting a potential role of this miRNA in DOX-induced cardiomyocyte toxicity. In this study, freshly isolated neonatal pig cardiomyocytes were used; following transfection of a miR-147-y mimic, the cell death induced by DOX was alleviated, represented by augmented mitophagy [indicated by a decrease in P62, and increases in LC3, PINK1, parkin mRNA, LC3II/I, beclin-1, PINK1, and parkin including p-parkin (Ser65) protein expression], prohibited cell apoptosis as determined by TUNEL staining, and the suppression of caspase-3 transcription and cleaved caspase-3 translation. In cells transfected with an miR-147-y inhibitor, DOX-induced mitophagy was decreased, while apoptosis was increased. Additionally, RAPTOR gene silencing in cardiomyocytes exposed to DOX increased the rate of mitophagy and decreased that of apoptosis as compared with the treatment with DOX alone. Moreover, RAPTOR overexpression downregulated the rate of mitophagy and increased that of apoptosis in cells exposed to DOX. RAPTOR was confirmed as the target gene of miR-147-y based on the results of luciferase reporter gene assays and the opposite effects of the miR-147-y mimic and miR147-y inhibitor on RAPTOR expression. In summary, our study suggests that miR-147-y mediates DOXinduced cardiomyocyte mitophagy while suppresses apoptosis by targeting RAPTOR, thus playing a protective role in DOX-induced cardiomyocyte damage.(c) 2022 Elsevier Inc. All rights reserved.
引用
收藏
页码:176 / 182
页数:7
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